This application is directed toward the development of a therapeutic drug conjugates with the intention of providing a cost effective adjunct to scaling and root planing procedures for the reduction of pocket depth in patients with adult periodontitis. This proposed study falls under an existing program announcement (PA-06-085) focusing on the "development of novel delivery systems for rapid and/or sustained, on-demand release of therapeutic agents (e.g., antimicrobial, anti-inflammatory, antibodies, peptides, nucleotides, small molecule receptor agonists/antagonists) in the oral cavity". To this end, the objective of this application will be to formulate and test the ability of several novel derivatives of an existing therapeutic agent that has proven to be effective against neutrophil-derived proteases in early testing, against several known periodontal pathogens and proteases. The major Specific Aims of this work are: 1) to test the effectiveness of the formulations to inhibit facultative anaerobes associated with periodontal disease and 2) to test their effectiveness in inhibiting the activities of bacterial and host-derived proteases that are believed to play major roles in this disease. This innovative and rational design resulted from the idea that addressing multiple biomolecular targets within the periodontal pocket environment should result in a more favorable environment for healing. Thus, the development of a biodegradable, cost-effective microsphere-based treatment for periodontitis that modulates an array of proteases and addresses bacterial burden is the subject of a clinical investigation. Public Health Significance: Periodontal disease is the most common chronic infectious disease in the world. In the U.S., a country known for good oral healthcare, more than 50 percent of adults have gingivitis and 35 percent have periodontitis. Dental disease has both a significant social and economic impact in the U.S. and is estimated to cause 189 million missed hours of work each year and expenses attributed to the disease of more than $60 billion. When the growing evidence that tooth and periodontal disease contributes to other costly systemic diseases such as cardiovascular, pulmonary, digestive and liver diseases, and preterm births, and diabetes are considered, the costs are significantly higher. [unreadable] [unreadable] [unreadable]